The epoxide-diol pathway in the metabolism of vinylbital in rat and man

Abstract

1. In urine of rats given vinylbital (5-vinyl-5-(1′-methylbutyl)barbituric acid) i.p., unchanged vinylbital and its devinylated metabolite, 5-(1′-methylbutyl)barbituric acid, were identified. Rats given synthetic 1′,2′-epoxyvinylbital excreted the same compound as a major metabolite. No unchanged epoxide, nor 1′,2′-dihydroxyvinylbital, could be identified in the urine of rats treated with vinylbital or its epoxide.

2. Attempts to synthesize 1′,2′-dihydroxyvinylbital from 1′,2′-epoxyvinylbital by acidic hydrolysis revealed that this possible metabolite decomposes readily to 5-(1′-methylbutyl)barbituric acid by a ‘retro-aldol type’ reaction.

3. In rat liver microsomal preparations 1′,2′-epoxyvinylbital is readily hydrated by epoxide hydratase, but this reaction is almost completely inhibited by 0.8mM 1,1,1-trichloropropene-2,3-oxide (TCPO). This finding and the identification of 5-(1′-methylbutyl)barbituric acid as end-product of this enzymic reaction provides further evidence for the existence of an epoxide-diol pathway in the metabolism of vinylbital.

4. Vinylbital and its devinylated metabolite are excreted in 36 h urine of rats treated with vinylbital, to an extent of 0.6±0.3 and 6.1±1.7% of the dose (n = 5), respectively. Upon administration of 1′,2′-epoxyvinylbital, 59.8±14.2% of the dose (n = 5) was excreted as 5-(1′-methylbutyl)barbituric acid.

5. In 60 h urine of three human volunteers who had taken 150mg of vinylbital orally, 2.6±1.7% of the dose was excreted as vinylbital and 11.0±4.1% as 5-(1′-methylbutyl)barbituric acid, illustrating that also in humans the epoxide-diol pathway plays a role in the metabolism of vinylbital.